Cannabinoid derivatives and methods for their preparation

Abstract

Novel compounds, pharmaceutical compositions containing these compounds, and methods for their pharmaceutical use are disclosed. In certain embodiments, the compounds are agonists and/or ligands of cannabinoid receptors and may be useful, inter alia, for treating and/or preventing pain, gastrointestinal disorders, genitourinary disorders, inflammation, glaucoma, auto-immune diseases, ischemic conditions, immune-related disorders, and neurodegenerative diseases, for providing cardioprotection against ischemic and reperfusion effects, for inducing apoptosis in malignant cells, and as an appetite stimulant.

What is claimed is: 
     
       1. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier, a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  and R 4  are each independently selected from hydrogen, hydroxyl, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, nitro, cyano, —OR 12 , —C(═O)R 12 , —C(═O)OR 12 , —OC(═O)R 12 , —OC(═O)OR 12 , —NHC(═O)R 12 , —N(R 13 )(R 14 ), —C(═O)N(R 13 )(R 14 ), —OC(═O)N(R 13 )(R 14 ), —NHC(═O)N(R 13 )(R 14 ), and —C(═O)CHR 15 N(R 13 )(R 14 ), each of which group may optionally be unsubstituted or substituted with one or more substituents, 
         R 2  is independently selected from —(C 1 -C 6 )alkyl, —C(═O)(C 1 -C 6 )alkyl, —C(═O)O(C 1 -C 6 )alkyl, —CN, —C(═O)NH(C 1 -C 6 )alkyl, —C(═O)N[(C 1 -C 6 )alkyl] 2 , —C(═O)CHR 15 NH(C 1 -C 6 )alkyl, and —C(═O)CHR 15 N[(C 1 -C 6 )alkyl] 2 ; 
         R 3  is hydrogen; or 
         R 1  and R 2 , and/or R 2  and R 5 , and/or R 2  and R 6 , and/or R 2  and R 7 , taken together with the carbon atoms to which each are attached, independently form a 4- to 8-membered ring, wherein 1 or 2 of the ring atoms independently are optionally replaced by —O—, —(C(═O)—, —(C(═O)O—, —NH—, —N(C 1 -C 6 )alkyl)-, —(C(═O)NH—, or —(C(═O)N(C 1 -C 6 )alkyl)-, and R 3  and R 4  are each independently selected from hydrogen, hydroxyl, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, nitro, cyano, —OR 12 , —C(═O)R 12 , —C(═O)OR 12 , —OC(═O)R 12 , —OC(═O)OR 12 , —NHC(═O)R 12 , —N(R 13 )(R 14 ), —C(═O)N(R 13 )(R 14 ), —OC(═O)N(R 13 )(R 14 ), —NHC(═O)N(R 13 )(R 14 ), and —C(═O)CHR 15 N(R 13 )(R 14 ), each of which group may optionally be unsubstituted or substituted with one or more substituents; 
         R 5 , R 5′ , R 6 , R 6′ , R 7 , R 7′ , R 8 , R 8′ , R 9 , and R 9′  are each independently selected from hydrogen, hydroxyl, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, nitro, cyano, —OR 12 , —C(═O)R 12 , —C(═O)OR 12 , —OC(═O)R 12 , —OC(═O)OR 12 , —NHC(═O)R 12 , —N(R 13 )(R 14 ), —C(═O)N(R 13 )(R 14 ), —OC(═O)N(R 13 )(R 14 ), —NHC(═O)N(R 13 )(R 14 ), and —C(═O)CHR 15 N(R 13 )(R 14 ), each of which group may optionally be unsubstituted or substituted with one or more substituents, or 
         R 5 , R 5′ , and/or R 6 , R 6′ , and/or R 7 , R 7′ , and/or R 8 , R 8′ , and/or R 9 , and R 9′  each independently form C═O, C═S, or C═NH, or 
         R 5  and R 6 , or R 5  and R 7 , or R 6  and R 7 , or R 6  and R 8 , or R 7  and R 8 , or R 7  and R 9 , or R 8  and R 9  taken together with the carbon atoms to which each are attached, independently form a 4- to 8-membered ring, wherein 1 or 2 of the ring atoms independently are optionally replaced by —O—, —(C(═O)—, —(C(═O)O—, —NH—, —N(C 1 -C 6 )alkyl)-, —(C(═O)NH—, or —(C(═O)N(C 1 -C 6 )alkyl)-, and the remainder of R 5  and R 6 , or R 5  and R 7 , or R 6  and R 7 , or R 6  and R 8 , or R 7  and R 8 , or R 7  and R 9 , or R 8  and R 9 , are each independently selected from hydrogen, hydroxyl, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, nitro, cyano, —OR 12 , —C(═O)R 12 , —C(═O)OR 12 , —OC(═O)R 12 , —OC(═O)OR 12 , —NHC(═O)R 12 , —N(R 13 )(R 14 ), —C(═O)N(R 13 )(R 14 ), —OC(═O)N(R 13 )(R 14 ), —NHC(═O)N(R 13 )(R 14 ), and —C(═O)CHR 15 N(R 13 )(R 14 ), each of which group may optionally be unsubstituted or substituted with one or more substituents; 
         A is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, 5- or 6-membered heterocyclic ring, 5- or 6-membered heteroaryl ring, and a 6-membered aryl ring, each of which group may be optionally unsubstituted or substituted with one or more substituents; 
         R 10  and R 11  are each independently selected from hydrogen, hydroxyl, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, spiroalkyl, cycloalkenyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, nitro, cyano, —OR 12 , —C(═O)R 12 , —C(═O)OR 12 , —OC(═O)R 12 , —OC(═O)OR 12 , —NHC(═O)R 12 , —N(R 13 )(R 14 ), —C(═O)N(R 13 )(R 14 ), —OC(═O)N(R 13 )(R 14 ), —NHC(═O)N(R 13 )(R 14 ), and —C(═O)CHR 15 N(R 13 )(R 14 ), each of which group may optionally be unsubstituted or substituted with one or more substituents, or R 10  and R 11 , taken together with the atom to which they are attached, independently form a substituted or unsubstituted 4 to 8 membered cyclic or heterocyclic ring, or a 5 membered heteroaryl ring, or a 6 membered aryl ring; 
         m and n are each independently an integer ranging from 0 to 5; 
         R 12  is each independently selected from hydrogen, hydroxyl, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, nitro, cyano, —N(R 13 )(R 14 ), —C(═O)N(R 13 )(R 14 ), —OC(═O)N(R 13 )(R 14 ), —NHC(═O)N(R 13 )(R 14 ), and —C(═O)CHR 15 N(R 13 )(R 14 ), each of which group may optionally be unsubstituted or substituted with one or more substituents; 
         R 13  and R 14  are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, or 
         R 13  and R 14 , taken together with the nitrogen atom to which they are attached, independently form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring atoms independently are optionally replaced by —O—, —S—, —S(═O)—, —S(═O) 2 , —NH—, —N(alkyl)-, —N(C(═O)R 12 )—, or —N(S(═O) 2 —R 12 )—; 
         R 15  is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and 
         at least one cannabinoid selected from Δ 9 -tetrahydrocannabinol and cannabidiol. 
       
     
     
       2. The pharmaceutical composition of  claim 1 , wherein A has formula: 
       
         
           
           
               
               
           
         
         wherein: 
         Q, E, G, J, L, and M are each independently selected from —C—, —CH—, —CR10-, —CR11-, —C═, —N—, —NH—, —NR10- —NR11-, —N═, —O—, and —S—, or one of Q, E, G, J, L, and M is and absent, and the other of Q, E, G, J, L, and M are each independently selected from —C—, —CH—, —CR10-, —CR11-, —C═, —N—, —NH—, —NR10- —NR11-, —N═, —O—, and —S—. 
       
     
     
       3. The pharmaceutical composition of  claim 1 , wherein R 1  and R 4  are each independently selected from hydrogen, —OR 12 , and —N(R 13 )(R 14 ). 
     
     
       4. The pharmaceutical composition of  claim 1 , wherein R 1  and R 4  are each independently selected from hydrogen, —OH, —O(C 1 -C 6 )alkyl, —NH(C 1 -C 6 )alkyl, and —N[(C 1 -C 6 )alkyl] 2 . 
     
     
       5. The pharmaceutical composition of  claim 1 , wherein R 2  and R 3  are each independently selected from hydrogen, —(C 1 -C 6 )alkyl, —C(═O)(C 1 -C 6 )alkyl, —C(═O)O(C 1 -C 6 )alkyl, —CN, —C(═O)NH(C 1 -C 6 )alkyl, —C(═O)N[(C 1 -C 6 )alkyl] 2 , —C(═O)CHR 15 NH(C 1 -C 6 )alkyl, and —C(═O)CHR 15 N[(C 1 -C 6 )alkyl] 2 . 
     
     
       6. The pharmaceutical composition of  claim 1 , wherein R 1  and R 4  are each independently selected from —OH and —O(C 1 -C 6 )alkyl; and R 2  and R 3  are each independently selected from hydrogen and —C(═O)(C 1 -C 6 )alkyl. 
     
     
       7. The pharmaceutical composition of  claim 1 , wherein R 5 , R 5′ , R 6 , R 6′ , R 7 , R 7′ , R 8 , R 8′ , R 9 , and R 9′  are each independently selected from hydrogen, —(C 1 -C 6 )alkyl, F, Cl, Br, I,—OH, and —O(C 1 -C 6 )alkyl. 
     
     
       8. The pharmaceutical composition of  claim 1 , wherein R 10  and R 11  are each independently selected from hydrogen and —(C 1 -C 6 )alkyl. 
     
     
       9. The pharmaceutical composition of  claim 1 , wherein R 10  and R 11  are each independently selected from hydrogen, —CH 3 , —CH 2 CH 3 , —CH═CH 2 , —CH 2 CH 2 CH 3 , —CH═CCH 3 , —CH 2 CH═CH 2 , —C═CHCH 2 CH 3 , —CH 2 CH═CHCH 3 , —CH 2 CH 2 CH═CH, —CH 2 CH(CH 3 ) 2 , —CH═C(CH 3 ) 2 , —CH 2 C(═CH 2 )(CH 3 ), —CH(CH 3 )CH 2 CH 3 , —C(═CH 2 )CH 2 CH 3 , and —CH(CH 3 )C═CH 2 .